Variation in the matrix metalloproteinase-3 gene in relation to atherosclerosis
Variation in the matrix metalloproteinase-3 gene in relation to atherosclerosis
In this study further investigations of the MMP-3 gene were undertaken in relation to atherosclerosis. Using the mutation scanning technique dideoxy fingerprinting (ddF), the promoter and coding regions of the MMP-3 gene were screened for unknown polymorphisms. Six new polymorphisms were identified using this method and confirmed by sequencing. Relative to transcription start site these were - 1986 T/C; - 1612 5A/6A; -1346 A/C; -709 A/G; -376G/C; and in exon 2, 802 A/G and 952 A/G. All six variants are single nucleotide polymorphisms (SNPs). Genotyping of these SNPs in unrelated individuals showed that they were in strong linkage disequilibrium with each other and with the previously identified 5A/6A polymorphism. The two commonest haplotypes were T-5A-A-A-G-A-A and C-6A-C-G-C-G-G. In a cohort of 913 patients with angiographically documented coronary artery disease (CAD), the 5A allele-containing genotypes were over-represented in patients with a history of MI (p=0.03). Furthermore, an association between the number of coronary arteries >50% stenosis and the 6A/6A genotype was observed (p=0.01).
To determine whether these polymorphisms affect MMP-3 promoter activity, transient transfection studies were performed using reporter genes for the two alleles of each individual polymorphism. Small but statistically significant differences of promoter activity were observed for each individual SNP. However, relative to the two commonest haplotypes, the common allele of three SNPs belonging to one haplotype conferred higher activity, whereas the common allele of the other two conferred lower activity.
These results suggest that individuals carrying the transcriptionally more active 5A allele are predisposed to the development of unstable plaques and CHD, whereas those carrying the transcriptionally less active 6A allele are more likely to develop stable but highly stenotic plaques.
University of Southampton
Beyzade, Seyyare
1762a4db-4300-4ef0-9140-a9bada45ccc3
2002
Beyzade, Seyyare
1762a4db-4300-4ef0-9140-a9bada45ccc3
Beyzade, Seyyare
(2002)
Variation in the matrix metalloproteinase-3 gene in relation to atherosclerosis.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
In this study further investigations of the MMP-3 gene were undertaken in relation to atherosclerosis. Using the mutation scanning technique dideoxy fingerprinting (ddF), the promoter and coding regions of the MMP-3 gene were screened for unknown polymorphisms. Six new polymorphisms were identified using this method and confirmed by sequencing. Relative to transcription start site these were - 1986 T/C; - 1612 5A/6A; -1346 A/C; -709 A/G; -376G/C; and in exon 2, 802 A/G and 952 A/G. All six variants are single nucleotide polymorphisms (SNPs). Genotyping of these SNPs in unrelated individuals showed that they were in strong linkage disequilibrium with each other and with the previously identified 5A/6A polymorphism. The two commonest haplotypes were T-5A-A-A-G-A-A and C-6A-C-G-C-G-G. In a cohort of 913 patients with angiographically documented coronary artery disease (CAD), the 5A allele-containing genotypes were over-represented in patients with a history of MI (p=0.03). Furthermore, an association between the number of coronary arteries >50% stenosis and the 6A/6A genotype was observed (p=0.01).
To determine whether these polymorphisms affect MMP-3 promoter activity, transient transfection studies were performed using reporter genes for the two alleles of each individual polymorphism. Small but statistically significant differences of promoter activity were observed for each individual SNP. However, relative to the two commonest haplotypes, the common allele of three SNPs belonging to one haplotype conferred higher activity, whereas the common allele of the other two conferred lower activity.
These results suggest that individuals carrying the transcriptionally more active 5A allele are predisposed to the development of unstable plaques and CHD, whereas those carrying the transcriptionally less active 6A allele are more likely to develop stable but highly stenotic plaques.
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Published date: 2002
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Local EPrints ID: 464927
URI: http://eprints.soton.ac.uk/id/eprint/464927
PURE UUID: 97aec915-b21c-4387-81d1-2d4f3d59318d
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Date deposited: 05 Jul 2022 00:11
Last modified: 16 Mar 2024 19:50
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Author:
Seyyare Beyzade
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